Microwave-assisted chemistry

The use of microwave heating in order to effect chemical transformations has grown rapidly in the last 10 years and is being widely used in combinatorial/ high-throughput approaches (Kappe, 2004 Hoz et al., 2005 Niichter et al., 2004  

Roberts and Strauss, 2005). As was described earlier, an added advantage to microwave chemistry is that often no solvent is required. In recent years, many commercial reactors have come on the market and some are amenable for scaling up reactions to the 10 kg scale. These new instruments allow direct control of reaction conditions, including temperature, pressure, stirring rate and microwave power, and therefore, more reproducible results can be obtained. For most successful microwave-assisted reactions, a polar solvent that is able to absorb the energy and efficiently convert it to heat is required, however, even solvents such as dioxane that are more or less microwave transparent can be used if a substrate, coreagent or catalyst absorbs microwaves well. In fact, ionic liquids have been exploited in this field as polar additives for low-absorbing reaction mixtures. 

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Microwave technology has now matured into an established technique in laboratory-scale organic synthesis. In addition, the application of microwave heating in microreactors is currently being investigated in organic synthesis reactions [9-11] and heterogeneous catalysis [12, 13]. However, most examples of microwave-assisted chemistry published until now have been performed on a... 

Recently, Hajek and coworkers have reported results on microwave-assisted chemistry performed by cooling of a reaction mixture to as low as -176 °C. Reaction rates were recorded under microwave and conventional conditions. The higher reaction rates under microwave heating at sub-ambient temperatures were attributed to a superheating of the heterogeneous K10 catalyst [44],... 

Most examples of microwave-assisted chemistry published to date and presented in this book (see Chapters 6 and 7) were performed on a scale of less than 1 g (typically 1-5 mL reaction volume). This is in part a consequence of the recent availability of single-mode microwave reactors that allow the safe processing of small reaction volumes under sealed-vessel conditions by microwave irradiation (see Chapter 3). While these instruments have been very successful for small-scale organic synthesis, it is clear that for microwave-assisted synthesis to become a fully accepted technology in the future there is a need to develop larger scale MAOS techniques that can ultimately routinely provide products on a multi kg (or even higher) scale. 

Vessels for microwave-assisted chemistry are usually made from thermal insulators such as PEEK, quartz, borosilicate glass or PTFE. Thus, the benefits of rapid heating can be diminished if the opportunity for workup is delayed by slow cooling. Decomposition of thermally unstable products also can occur. 

Despite the area of microwave-assisted chemistry being 20 years old, the technique has only recently received widespread global acceptance. This is a consequence of the recent availability of commercial microwave systems specific for synthesis, which offer improved opportunities for reproducibility, rapid synthesis, rapid reaction optimisation and the potential discovery of new chemistries. The beneficial effects of microwave irradiation are finding an increased role in process chemistry, especially in cases when usual methods require forcing conditions or prolonged reaction times. 

The microwave-assisted chemistry of a variety of aromatic heterocycles has been extended to the synthesis of fused molecules which share, at least, one heteroatom. In this area, the synthesis of nitrogen containing compounds has been actively investigated. All the compounds described below have been prepared in an effort to find compounds with interesting biological activity. 

Stadler, A. and Kappe, C.O., Automated library generation using sequential microwave-assisted chemistry. Application toward the Biginelli multicomponent condensation, /. Comb. Chem., 2001, 3,624-630. 

The combination of microwave-assisted chemistry and solid-phase synthesis applications is a logical consequence of the increased speed and effectiveness offered by microwave dielectric heating. While this technology is heavily used in the pharmaceutical and agrochemical research laboratories already, a further increase in the use of microwave-assisted solid-phase synthesis both in industry and in academic laboratories can be expected. This will depend also on the availability of modern microwave instrumentation specifically designed for solid-phase chemistry, involving for example dedicated vessels for bottom filtration techniques. 

A. Corsaro, U. Chiacchio, V. Pistara, and G. Romeo, Microwave-assisted chemistry of carbohydrates, Curr. Org. Chem., 8 (2004) 511-538. 

Camptothecin was irradiated under solvent-free conditions for 7 min at the full power of the microwave oven (Scheme 28). The product, Mappicine ketone, was isolated in 96% yield without a trace of undesired side products, which clearly exhibits the potential of microwave-assisted chemistry. In comparison, when the reaction was run at rt in THF and in the presence of BF3 x Et20, Mappicine ketone was isolated in a mere 65% yield. 

In addition to the use in the synthesis of potential hepatitis C drugs, microwave-assisted chemistry has also been used in the synthesis of mast cell tryptase inhibitors, thrombin inhibitors, and Factor Xa inhibitors. The trypsin-like serine protease tryptase is the major secretory product of human mast cells and has been implicated as an inflammatory mediator in a number of conditions, especially asthma. Once released upon mast cell activation, the tryptase cleaves substrates that otherwise cause smooth muscle relaxation and thereby bronchi- and vasodilation. It is therefore not surprising that numerous reports on low molecular weight tryptase inhibitors have appeared. 

With these results in hand, several examples in carbohydrate chemistry have been performed including glycosylations, peracetylations, saponifications, and epoxidations of glucose derivatives. Within 2-10 min (depending on the chemistry and the scale) 60-220 g of the desired compounds have been generated, showing the easy access of products in the multigram level by solventless microwave-assisted chemistry [37]. 

Comment. The Bose group at Stevens Institute of Technology, New Jersey, has been especially active in applying microwave-assisted chemistry to the preparation and further transformation of p-lactam synthons into other lactams, Taxol 7 precursors, amino sugars, and hydroxyamino acids.78 Some steric control has been observed.78(c)... 

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